Objective To investigate the clinical characteristics of patients with early gastric cancer (EGC) at different lesion sites, and to analyze the postoperative efficacy, safety and medium-term prognosis after endoscopic submucosal dissection (ESD). Methods A total of 104 EGC patients who received ESD treatment in our hospital from January 2021 to December 2024 were enrolled. According to lesion location, the patients were divided into cardia group (5 cases), gastric fundus group (8 cases), gastric body group (9 cases), gastric angular group (29 cases) and gastric antrum group (53 cases). General baseline data, admission diagnosis, pathological risk grade, treatment efficacy, surgical safety and short-term and medium-term prognosis were compared among all groups. Results There were no significant differences in age, composition of admission diagnosis and pathological risk grade (low-risk vs. high-risk pathology) among patients with different lesion sites (all P>0.05). The overall difference in gender composition among groups was at a critical level (Pearson chi-square=9.464, P=0.050). Combined with the results of likelihood ratio chi-square test (likelihood ratio chi-square=11.916, P=0.018), the difference in gender distribution was statistically significant. The en bloc resection rate of ESD was 100.00% in all groups, while significant intergroup differences were found in complete resection rate and curative resection rate (all P<0.05). No significant differences were observed in the incidence of postoperative bleeding and perforation after ESD across groups (all P>0.05). The 1-year survival rate was 100.00% in all groups; no significant difference was detected in the 1-year recurrence rate (P>0.05). Due to the limitation of sample size, the 3-year follow-up data were only analyzed descriptively. The 3-year recurrence rate of the cardia group and gastric fundus group was 100.00%, with a 3-year survival rate of 0.00%, and no death occurred in the other groups. Conclusion The anatomical lesion site of EGC is correlated with gender distribution, postoperative efficacy of ESD and medium-term prognosis. It is recommended to optimize the refined surgical manipulation for lesions in the cardia and gastric fundus, and strengthen targeted postoperative follow-up for patients with cardiac lesions to reduce the risk of tumor recurrence.